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Abstract

BACKGROUND: Rapid delivery of potent opioid to the systemic circulation is an important feature for the effective treatment of acute and acute-on-chronic breakthrough pain. The delivery of different opioids by the pulmonary route has been inconsistent, usually resulting in low bioavailability of the drug. Staccato® Fentanyl for Inhalation is a handheld inhaler producing a single metered dose of aerosolized fentanyl during a single inspiration. The aerosol is of high purity (≥98%) at a particle size (1 to 3.5 microns) shown to be best for pulmonary absorption.

METHODS: We conducted the study in healthy volunteers in 2 stages. In the crossover stage, 10 subjects received IV fentanyl 25 µg and inhaled fentanyl 25 µg on separate occasions. The dose escalation stage was a multidose, randomized, double-blind, placebo-controlled, single-period dose escalation study of inhaled fentanyl (50 to 300 µg). Serial blood sampling was performed over an 8-hour period after drug administration to determine the pharmacokinetic profile, and serial pupillometry was performed as a measure of pharmacodynamic effect.

RESULTS: In the crossover stage the pharmacokinetic profiles of the inhaled and IV fentanyl showed similar peak arterial concentrations and areas under the curve. The time to maximum concentration was slightly shorter for the inhaled than IV fentanyl, 20.5 and 31.5 seconds, respectively. In the dose escalation stage the administration of repeated doses resulted in predictable, dose-dependent serum concentrations.

CONCLUSIONS: This study has demonstrated that the pharmacokinetic profile of single doses of inhaled fentanyl is comparable to IV administration.

Rapid delivery of potent opioids to the systemic circulation is an important feature for the effective treatment of acute and acute-on-chronic breakthrough pain.1–3 Fentanyl has been delivered via the sublingual, buccal, and inhaled routes.1,4–6 Several studies have attempted to deliver different opioid analgesics by the pulmonary route for rapid systemic action.7 The large surface area of the lung available for inhaled drug absorption is a potentially attractive route of delivery when rapid onset of action is important.7–13 However, the lack of success with pulmonary administration of opioid analgesics may be due to the complexity of the apparatus, and the difficulty of timing inspiration of the drug delivery systems used, rather than to characteristics of the drugs themselves. For example, Chrubasik et al. reported that pulmonary delivery of nebulized morphine could be as effective as the IV route,14 but the mean bioavailability was 17%. Dershwitz et al. reported a bioavailability of 59%.15 Other investigators have also reported similar low bioavailability via nebulization with drugs such as fentanyl.8,9

Staccato® Fentanyl for Inhalation is a combination drug–device delivery system for rapid, systemic delivery of aerosolized fentanyl via the lung. The product is a handheld inhaler containing a disposable dose cartridge of fentanyl layered upon a metal foil (Fig. 1). A single metered dose of fentanyl is administered during a single inspiration. An electric current is passed through a single metal foil to produce a thermally generated aerosol, producing rapid heating of the foil and the overlying drug film.16–20 The drug vaporizes, producing a fentanyl aerosol of high purity (>98%) at optimal particle size (1 to 3.5 microns).20 The use of the thin drug film facilitates vaporization without significant drug degradation during the rapid heating.

The objectives of this study were to investigate the pharmacokinetics (PK) and pharmacodynamics of inhaled fentanyl in healthy human subjects. Prospectively specified objectives included the following: (1) assess absolute bioavailability on the basis of the geometric mean ratios and 90% confidence interval (CI) on the ratio of area under the curve (AUC) (0 to infinity) AUCinf (aerosol)/AUCinf (IV); and (2) assess dose proportionality by power analysis (linear regression of log AUCinf versus log dose). Dose proportionality will be confirmed if the 90% CI on the slope of log AUC versus log dose is within 0.8 to 1.25.

METHODS

Study Subjects

After approval of the study protocol by the IRB, written informed consent was obtained from healthy adult subjects. Eligible volunteers were men and women ages between 18 and 55 years with normal findings on medical history, physical examination (height, weight, vital signs, spirometry, and 12-lead electrocardiogram [ECG]) and clinical laboratory tests (hematology, serum chemistry, negative serum pregnancy test [women only]) within 2 weeks before enrollment in the study. Normal spirometry was defined as forced expiratory volume in 1 minute (FEV1) ≥ 80% of predicted value. Volunteers were required to have a negative urine drug screen (cannabinoids, opiates, amphetamines, cocaine, barbiturates, and benzodiazepines) and a negative serum alcohol and to have been nicotine- and tobacco-free for at least 12 months before enrollment. Prescription and over-the-counter medications were prohibited for 5 days before dosing and during the study (with the exception of steroidal contraceptives for women and acetaminophen).

At the screening visit, each subject viewed a 5-minute training video, the investigator demonstrated how to inhale on an inspirometer, and the subjects demonstrated that they could generate adequate flow and volume on the inspirometer. On the treatment visit, subjects again demonstrated competence with the inspirometer.

Study Design

The study was conducted in 2 stages. Crossover stage (cohort A) was a single dose, open label, 2-period crossover comparison of IV fentanyl to inhaled fentanyl. Half of the subjects (n = 5) received 25 µg of IV fentanyl over a 5-second period during period 1, followed by a 2-week washout. They then received a single 25-µg dose of inhaled fentanyl in period 2. The other half received the same treatments in the reverse order. The dose escalation stage was a multidose, randomized, double-blind, placebo-controlled, single-period dose escalation study of inhaled fentanyl. This ascending dose escalation study comprised 5 cohorts (cohort A + cohorts B–E). Cohorts B–E received fentanyl doses of 25 µg every 4 minutes ×2 (50 µg), ×4 (100 µg), ×6 (150 µg), and 12 (25 µg every 4 minutes × 6 twice with a 40-minute interval between doses 6 and 7 300 µg). Total fentanyl doses were thus 50 to 300 µg given over 4 to 80 minutes. Both the 4-minute lockout interval and the maximum of 6 doses per hour reflect the planned use of the device for patient-controlled analgesia delivery. Within each cohort of 10 subjects, 8 were randomly assigned to active inhaled fentanyl, and 2 were randomly assigned to placebo. The device in the placebo group was identical to that in the active group.

Study Conduct

Subjects were fasted in accordance with ASA Practice Guidelines for Preoperative Fasting and were allowed clear liquids until 2 hours before dosing. At 1 hour after the last dose administration, subjects were permitted to drink water. Subjects were fed at 4 hours and at 10 hours after the last dose.

Subjects received instruction in Staccato inhaler use at screening. This was repeated on the study day. The device was put in a ready state by depression of the on button. Subjects were instructed to exhale fully, then put the mouthpiece between their lips and inhale briskly and completely through the device. A flow sensor located within the device actuated the delivery of the dose as soon as the flow rate exceeded 2.5 L/min. The subjects inhaled to maximum inspiratory capacity and then held that breath for a timed period of up to 10 seconds. Immediately after each inhalation and breath hold, the subject then exhaled into the supplied exhalation filter to collect any exhaled aerosol.

Blood samples (6 mL) for measurement of serum fentanyl concentrations were collected from the arterial catheter in serum separator tubes with clot activator at predose, every 15 seconds for the first 2 minutes, at 3, 4, 5, 7.5, 10, 20, 30, and 45 minutes, and at 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, and 8 hours after study drug administration (after each dose in cohort A crossover study, the last dose in cohorts B–E). All samples were centrifuged and the serum extracted. The samples were frozen at −80°C until analyzed. Serum fentanyl concentrations were measured by liquid chromatography–tandem mass spectrometry (MDS Pharma Services, Lincoln, NE) with a lower limit of quantification of 10 pg/mL. Precision of the assay was <5.1%; accuracy across runs ranged from –5.7% to 0.7%. The mean coated dose and mean emitted dose were in vitro (laboratory) determinations from samples taken from the same lot as used for the study. The coated dose was assayed from fentanyl washed from the device. The emitted dose was assayed from the air emitted from the device under standard test conditions.

Pharmacokinetic Measures

Serum concentrations were used to estimate the following PK variables: area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUCinf), AUC from time 0 to time tlast, i.e., the last quantifiable concentration (AUClast), maximum observed serum concentration (Cmax), observed time of Cmax (Tmax), terminal phase elimination rate constant (ke), apparent terminal elimination half-life calculated from ke (T1/2), apparent total body clearance/fraction absorbed (Cl/F) calculated from AUC, and dose. The absolute bioavailability was assessed on the basis of the geometric mean ratios and 90% CI of the individual subject ratios of AUCinf (inhaled)/AUCinf (IV–5 seconds).

Noncompartmental analyses (NCA) were done with WinNonlin version 5.0.1 and all other analyses via SAS version 8.2 for Windows.

Pharmacodynamic Measures

The primary pharmacodynamic variable was pupil diameter. Serial pupillometry measurements were taken with the handheld Neuroptics 5900 pupillometer (Neuroptics, Inc., Irvine, CA). An eye patch was placed over the nonmeasured eye to exclude ambient light. The pupillometer was placed over the measured eye and its position adjusted until the eye was correctly aligned within the LCD screen of the pupillometer. Three measurements were taken predose and averaged to provide the baseline pupil diameter. Subsequent pupil measurements were taken at 1, 2, 3, 5, 7.5, 10, 20, and 30 minutes, and at 1, 2, 4, 5, 6, 7, and 8 hours after study drug administration (after each of the doses cohort A crossover and last dose in cohorts B–E). In addition, pupil measurements were taken 2 minutes before each dose administration (cohorts B–E only).

RESULTS

Fifty-one subjects were enrolled in the study. One subject in cohort B was removed from the study because the arterial access was lost after treatment, but before any PK samples had been taken. This subject was subsequently replaced. In 1 subject (cohort C), blood samples were improperly stored, and these samples were not assayed. The demographics of the study subjects are summarized in Table 1.

Crossover Stage (Cohort A)

The PK profiles are shown in Figure 2. These PK profiles show kinetics comparable to IV administration with similar peak arterial concentrations (Cmax) and AUC parameters (Table 2). The mean pupil diameter at baseline ranged from 6.60 to 7.35 mm. In cohort A, pupillometry exhibited a clear miosis response to 25 µg fentanyl with similar patterns when delivered by IV and inhalation routes (Fig. 2, 2C and 2D).

For the dose cartridges used in this study, in vitro assessment determined that the mean emitted dose of fentanyl was 23.4 µg (93.5% of the 25 µg dose given IV). The mean ± sd exhaled aerosol was 3.1% ± 3.3%.20 The absolute bioavailability of fentanyl, based on mean emitted dose AUCinf, was 96.8% (90% CI, 84.3% to 111%), which lies entirely within the criteria range of 80% to 125%. Figure 3 shows these results, and Table 2 shows the associated PK parameters and ratios.

Dose Escalation Stage (Cohorts B–E)

Fentanyl concentrations over time by dose group are shown in Figure 4. Pupillometry exhibited a clear miosis for each of the dose groups and a dose-related increase in the mean response across the dose groups (Fig. 4, 4C and 4D).

Dose proportionality using the power method (linear regression of log AUCinf vs log dose) shown in Figure 5 had a slope (90% CI) of 1.12 (1.04–1.20). Since subject weight did not have a statistically significant contribution to the regression, the above result is the primary measure of dose proportionality. This 90% CI is well within the criteria for dose proportionality (0.80–1.25). AUCinf and associated PK variables are shown by dose in Table 3.

No clinically significant changes in NIBP, heart rate, or Spo2 were observed. The safety screen for the pulmonary route of administration was the comparison of the changes from baseline in FEV1 and forced vital capacity as a function of dose (including placebo). No observable dose-related trends were identified for FEV1 or forced vital capacity. None of the 90% CIs on the changes from baseline excluded zero.

There were no unexpected side effects. Nine subjects (15%) reported 1 or more adverse events (total 10), none of which was serious. Two events were related to the indwelling arterial and IV catheters and were unrelated to the drug. The remaining 8 adverse events were associated with nausea (1 mild, 6 moderate) and vomiting (1 moderate). The highest incidence of nausea (4 subjects) was seen in the group receiving 300 µg fentanyl. Most nausea events did not require any intervention, and those that did responded to standard antiemetic regimens.

DISCUSSION

This study has demonstrated that single-breath delivery of fentanyl using the Staccato system results in a PK profile identical to IV administration of a similar dose of fentanyl in terms of onset, extent, and reliability of absorption, especially during the initial phase (Fig. 2). Furthermore, the administration of repeated doses resulted in predictable, dose-dependent serum concentrations.

Of particular interest is the rapid absorption of inhaled fentanyl. This is the first study to show that the absorption via the inhaled route is as fast as IV administration. The measured drug serum concentrations showed a median Tmax at 20.5 seconds for inhaled and 31.5 seconds for IV fentanyl administered over 5 seconds. This would suggest extensive delivery of the drug to the distal airways with rapid absorption across the alveolar membrane into the pulmonary capillaries. The difference in Tmax probably reflects the circulation time needed for the IV dose to reach the arterial sampling catheter from the venous administration site and is not considered clinically important.

In the crossover stage, a similar reduction in pupillary size was seen with equal doses of Staccato and IV fentanyl. In the dose-escalation stage, the reduction in pupillary size exhibited a dose-related increase with fentanyl doses. In cohort E (300 µg fentanyl) the effect was similar to that in cohort D (150 µg fentanyl), which probably reflects the 40-minute separation between doses 6 and 7 or a ceiling effect in pupillary response. The pupillometry findings from this study were consistent with those reported by Ibrahim et al.21

The side effect profile of inhaled fentanyl is consistent with the known side effects of opioids, namely nausea and vomiting. The most frequent side effect reported was nausea, seen at the higher dose ranges. One potential side effect of inhaled drug delivery is bronchoconstriction from direct airway irritation. Subjects were prescreened to exclude reactive airway disease. No subjects reported any symptoms, and serial spirometry was unaltered.

Previous studies of nebulized morphine and fentanyl have reported markedly low bioavailability of 17%, 59%, and 12%, respectively. Improvements in the design of delivery systems have significantly improved lung deposition of opioid and consequently better serum concentrations. Mather et al.22 studied the delivery of fentanyl using a microprocessor-controlled metered-dose inhaler. This study reported a high bioavailability (~100%) when similar doses were administered IV and by inhalation. However, both the serum fentanyl Cmax and the Tmax were significantly different, by approximately 50%.

Fentanyl is a potent synthetic opioid with greater lipophilicity than other opioids, rendering it a suitable candidate for pulmonary delivery. Inhaled administration of liposomal fentanyl has been studied by Hung et al.23 They reported the administration of a formulation in which 50% of the fentanyl was bound to liposomes and the remainder was free. The Cmax for the encapsulated liposomal formulation was significantly lower than the IV dose, but the encapsulated liposomal formulation did have higher serum fentanyl concentrations at 8 and 24 hours, thus making it unsuitable for the management of acute pain.

Several systems for delivery of fentanyl via oral mucosa have been studied. In the study conducted by Darwish et al.,24 comparing the PK profiles of identical total doses of fentanyl, given as either 1 or 4 fentanyl buccal tablets, the median Tmax for both was 45 minutes. A fentanyl 200-µg sublingual spray study in healthy volunteers by Tansley et al.25 showed a Tmax of 40 minutes, Cmax of 0.347 ng/mL, AUCinf of 129.9 ng · min/mL, and absolute bioavailability of 77.7%.

Our study has some limitations. The delivery of the drug to the distal airways is dependent upon several factors: patency of proximal and intermediate airways, intact thoracic wall, ability to generate adequate inspiratory effort, and adequate respiratory drive. At present the effects of different disease processes upon delivery via inhalation, either singularly or in combination, are unknown. The study was performed in healthy, nonsmoking volunteers, and the efficacy of inhaled fentanyl has not been measured in patients with acute postoperative pain or in patients with breakthrough cancer pain or in smokers. However, it is reasonable to assume that the analgesic profile of inhaled fentanyl would be similar to that of IV fentanyl in these patient populations. In addition, this extremely rapid onset, highly bioavailable, potent opioid delivery system may be a source of opioid diversion. Although this is outside the scope of this study, this issue has to be addressed before the system is available to patients.

In conclusion, our study has demonstrated that the PK profile of single doses of inhaled fentanyl is comparable to that of IV administration. Further studies are warranted to assess the utility of this delivery system in patients.

DISCLOSURES:

Name: David B. MacLeod, FRCA.

Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.

Attestation: David MacLeod approved the final manuscript. David MacLeod attests to the integrity of the original data and the analysis reported in this manuscript. David MacLeod is the archival author.

Conflicts of Interest: Department of Anesthesiology received research funding from Alexza Pharmaceuticals.

Name: Ashraf S. Habib, MB, ChB, FRCA.

Contribution: This author helped conduct the study, collect the data, and prepare the manuscript.

Attestation: Ashraf Habib approved the final manuscript.

Conflicts of Interest: The author has no conflict of interest to declare.

Name: Keita Ikeda, PhD.

Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.

Attestation: Keita Ikeda approved the final manuscript.

Conflicts of Interest: The author has no conflict of interest to declare.

Name: Daniel A. Spyker, PhD, MD.

Contribution: This author helped design the study, analyze the data, and prepare the manuscript.

Attestation: Daniel Spyker approved the final manuscript. Daniel Spyker attests to the integrity of the original data and the analysis reported in this manuscript.

Conflicts of Interest: Daniel Spyker was a full-time employee of Alexza during study design, conduct, and reporting, and has Alexza stock and stock options.

Name: James V. Cassella, PhD.

Contribution: This author helped design the study and prepare the manuscript.

Attestation: James Cassella approved the final manuscript.

Conflicts of Interest: James Cassella was a full-time employee of Alexza during study design, conduct, and reporting, and has Alexza stock and stock options.

Name: Kok Yuen Ho, MBBS, MMed.

Contribution: This author helped conduct the study, collect the data, and prepare the manuscript.

Attestation: Kok Yuen Ho approved the final manuscript.

Conflicts of Interest: The author has no conflict of interest to declare.

Name: Tong J. Gan, FRCA.

Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.

Attestation: Tong Gan approved the final manuscript.

Conflicts of Interest: Department of Anesthesiology received research funding from Alexza Pharmaceuticals.

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